SRA deficiency induces follicular dysplasia by disrupting the hypothalamic Kisspeptin-GPR54 system in mice

Abstract Purpose To investigate how steroid receptor RNA activator (SRA) regulates follicular development in mice. Methods Systemic SRA knockout mice were introduced. SRA expression was reinstated in the anteroventral periventricular nucleus (AVPV) of the hypothalamus using lentiviral vectors. Subsequently, the estrous cycle, serum hormone levels, follicle development, and hypothalamic kisspeptin expression in mice were assessed. Kiss1 promoter activity was tested with a fluorescent reporter system in Neuro-2a cells. Results SRA deficiency caused a shift to shorter metestrus and longer diestrus phases, reduced numbers of large antral and preovulatory follicles, increased formation of atretic cyst-like follicles, lowered serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E2), and decreased expression of hypothalamic AVPV-kisspeptin in mice. The reinstatement of SRA expression in the AVPV nucleus normalized kisspeptin expression, hormone levels, and follicle development. In Neuro-2a cells, SRA increased Kiss1 transcription upon E2 treatment, a response that was nullified by the estrogen receptor alpha (ERα) inhibitor. Conclusion SRA enhances ERα-mediated Kiss1 transcription in the AVPV nucleus to control the kisspeptin-GPR54 system in hypothalamus, essential for regulating ovulation through the hypothalamus-pituitary-ovary axis.